Title

Author

Degree Type

Dissertation

Date of Award

2001

Degree Name

Doctor of Philosophy

Department

Biomedical Sciences

First Advisor

Srdija Jeftinija

Second Advisor

Anumantha Kanthasamy

Abstract

For decades, astrocytes, the most numerous cell of the central nervous system, were considered to be passive supporters of nerve cell architecture and function, lacking excitability and having no role in signal integration. However, recent findings have progressively challenged that view, highlighting the active participation of astrocytes in synaptic transmission and information processing. This dissertation presents evidence for the major contribution of astrocytes in the modulation of neuronal excitability that is in large part mediated by the excitatory neurotransmitter glutamate. Neuroligands, ATP and SDF-1alpha released glutamate from astrocytes that stimulated adjacent neurons by the NMDA-receptor activation. Furthermore, rapid bi-directional signaling loops between the neurons and glia have been revealed in experiments performed on co-cultures.;In addition to its fundamental physiological importance, this dissertation postulates a new role for astrocytes in brain pathology. Cell culture experiments revealed a direct toxic effect of neurotoxins, gp120, an HIV-1 envelope glycoprotein, and cannabinoids on astrocytes. A propensity of astrocytes to undergo apoptosis and to release excitotoxic glutamate in response to insult elicited by gp120 and cannabinoids suggests that, along with neurons, astroglia are an important site of action for neurotoxins in brain. Potential mechanisms of cannabinoid toxicity include formation of ceramide and free radicals and activation of several primary and secondary effector enzymes. An indirect contribution of astrocytes to the gp120 and cannabinoid-induced neuron injury is implied with this study. Potential mechanisms include disturbances of glia function and their ability to support neurons and the astrocytes-mediated excitotoxins formation in the brain. This part of the dissertation gave well-deserved respect to the issue of cannabinoid and gp120 astrotoxicity because a better understanding of the pathogenesis of astrocytes in encephalopathies may have important therapeutic implications in the future.